Highly efficient oxidation of 2-imidazoline-5-carboxylic derivatives to imidazole-5-carboxylic derivatives by dioxygen

Article abstract of DOI:10.1016/j.tet.2012.01.025

A highly efficient and environmental-benign oxidation by dioxygen (or air) as the sole oxidant was first applied for the conversion of 2-imidazoline-5- carboxylic derivatives to imidazole-5-carboxylic derivatives in very good and excellent yields. The sub

Full text of DOI:10.1016/j.tet.2012.01.025

Tetrahedron 68 (2012) 3123e3128
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Highly efficient oxidation of 2-imidazoline-5-carboxylic derivatives
to imidazole-5-carboxylic derivatives by dioxygen
*
Yue Huang, Xiaodong Zu, Fan Wu, Jinyi Xu, Xiaoming Wu, Hequan Yao
State key Laboratory of Natural Medicines and department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 October 2011
Received in revised form 31 December 2011
Accepted 13 January 2012
Available online 20 January 2012
A highly efficient and environmental-benign oxidation by dioxygen (or air) as the sole oxidant was first
applied for the conversion of 2-imidazoline-5-carboxylic derivatives to imidazole-5-carboxylic de-
rivatives in very good and excellent yields. The substituent effect on 2-imidazoline ring was investigated.
This protocol was also suitable for the synthesis of 2-imidazoles in relatively large scale.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Oxidation
2-Imidazoline
Imidazole
Dioxygen
Scalable
1. Introduction
their further application to the synthesis of the desired products. For
an economical and environmental viewpoint, a clean, and efficient
Nitrogen-containing heterocyclic compounds, such as thiazoles,
oxazoles, and imidazoles are important motifs of pharmaceuticals
and functional materials, which attracted much attention of syn-
thetic community.1,2 Typically, thiazoles, oxazoles, and imidazoles
with carboxylic functional groups at 4 or 5-position are often found
in a number of naturally occurring products and synthetic mole-
cules with interesting biological activities, such as antiviral, anti-
fungal, antibacterial, antihypertensive, anti-inflammatory, and
anti-tumor activities.2e4
oxidation process is thus extremely valuable and will be more ap-
plicable to industrial application.
In 2011, Wang and Blechert disclosed one example on the
photocatalyzed oxidation of 2-imidazoline using carbon nitride and
dioxygen (0.5 MPa).18 Recently, we have demonstrated more simple
method for the oxidation of 2-thiazolines and 2-oxazolines using
dioxygen as a sole oxidant (Scheme 1, Eq. 1 and Eq. 2).19 In this
paper, we wish to extend our environmental-benign system to the
oxidation of 2-imidazoline-5-carboxylic derivatives.20 (Eq. 3).
In the past decades, many approaches have been developed for
the synthesis of azoles including imidazoles. Among these, oxidative
dehydrogenation of imidazolines to imidazoles was one of the most
general and reliable methods for the preparation of imidazoles. Up to
date, various reaction systems, such as DBU/CBrCl3,5 ZneAl2O3,6 Ni,7
Se,8 Pd/C,9 MnO2,10 BaMnO4,11 DMSO/(COCl)2,12 KMnO4/Al2O3,13 o-
iodoxybenzoic acid (IBX),14 (diacetoxiodo)benzene (DIB)/K2CO3,15
17
NaIO4eMn(salophen)Cl,16 and KMnO4/SiO2 are proved to be very
useful for the oxidative dehydrogenation of imidazolines. However,
all above systems have at least one or more drawbacks, such as low
yields of products, excess amount of reagents, expensive reagents or
catalysts, and hazardous reaction conditions. Also, the drawbacks of
some reagents, which are toxic or difficult to dispose somewhat limit
* Corresponding author. Tel.: þ86 25 83271042; e-mail address: hyao@cpu.
Scheme 1. Oxidation of 2-azolines to azoles with dioxygen.
edu.cn (H. Yao).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.025

3124
Y. Huang et al. / Tetrahedron 68 (2012) 3123e3128
Table 2
2. Results and discussion
Oxidation of 2-imidazoline-5-carboxylates to imidazole-5-carboxylatesa,b
We chose 5a as a substrate bearing 5-carboxylate group under
the conditions we previous used for the oxidation of 2-thio(oxa)
zoline-carboxylates, in which potassium carbonate (3 equiv) was
used as a base, anhydrous DMF was used as a solvent and dioxygen
or air was used as a sole oxidant. As shown in Table 1, high yields of
the desired product 6a could be achieved under either air or O2
atmosphere (entries 1e4). Remarkably shorter reaction time was
needed for molecular oxygen or air to fully oxidize 5a at 100 ꢀC than
at 80 ꢀC. We also demonstrated the reaction was less effective in
other solvents (entries 5e10). Although we reported that the oxi-
dation for 2-azoline-4-carboxylates was stepwise based on the
isolated intermediates,19a we were not able to observe any in-
termediate in this case, even at lower temperature or in shorter
reaction time. This may be explained that the intermediate is not
stable enough to be seen or isolated under the oxidation condition.
With these encouraging results, we evaluated the substrate
scope. As shown in Table 2, various 2-imidazoline-5-carboxylates20
with aryl groups could be converted to the corresponding products
and all reactions could complete in less than 10 h using molecular
oxygen as an oxidant (entries 1e12, condition A). Good to excellent
yields of the corresponding products were achieved for all sub-
strates bearing electron-deficient or halo-substituted aryl groups
(entries 3e6), while moderate yields for the ones bearing electron-
rich aryl groups (entries 7e9). An exception was that 6b bearing 4-
nitrophenyl substituent at 2-position was obtained in relatively low
yield after flash column chromatography. Although the reaction of
5b was clean, the poor solubility of 6b in various organic solvents,
such as EtOAc, CH2Cl2, Et2O, and CHCl3, might cause incomplete
extraction from the reaction mixture and incomplete elution from
the column, leading to the relatively low isolated yield of 6b. No
obvious hydrolysis of the ester groups was observed in all cases.
The good yields could also maintain for the substrates with slightly
bulky esters (entries 10e12). When the reactions were conducted
with air, the corresponding products were also obtained in good
yields, albeit longer reaction time was required (entries 1e12,
condition B). These results in Table 2 indicated that electron-
deficient aryl group on 2-imidazoline ring could facilitate this ox-
idation process, which is consistent with our previous results.19a,19b
Next, we examined the oxidation of the substrates bearing
carboxamide group at 5-position. We first tried to conduct the re-
action with pure dioxygen as an oxidant (entries 1e4, Table 3). Very
interestingly, the reactions did not proceed as well as we expected.
The substrate 7a was not fully consumed even after prolonged
Entry
1
Product
Conditionb Time (h) Yieldc (%)
A
B
2.5
10
93
89
A
B
10
13
67
61
2
3
A
B
5
11
84
87
A
B
5
8
94
91
4
5
6
7
8
9
A
B
6
8
95
93
A
B
2.5
5
93
91
A
B
4
11
92
87
A
B
7
21
73
73
A
B
9
27
73
74
A
B
4
8
92
94
10
11
A
B
2
2.5
90
94
Table 1
A
B
4
10
92
90
The screening of reaction conditions of oxidation of imidazoline-5-carboxylatea,b
12
a
Reactions were performed in DMF on a 0.5 mmol scale with K2CO3 (3 equiv) and
molecular sieves (4 A, 200 wt %) at 100 ꢀC.
ꢀ
b
Condition A: the reaction was performed with O2 (balloon). Condition B: the
Entry
Conditions
Temp (ꢀC)
Time (h)
Yieldc (%)
reaction was open to air.
c
Isolated yields.
1
2
3
4
5
6
7
8
9
10
DMF, K2CO3, O2
DMF, K2CO3, air
DMF, K2CO3, O2
DMF, K2CO3, air
DME, K2CO3, O2
DME, K2CO3, air
DCM, K2CO3, O2
DCM, K2CO3, air
CH3CN, K2CO3, O2
CH3CN, K2CO3, air
80
80
100
100
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
10
16
2.5
5
24
24
24
24
24
24
91
91
93
89
26
24
Trace
Trace
21
reaction time (36 h). Considering that the carboxamide group is
stable under basic condition, we then tried strong base, such as
NaOH to promote this reaction. To our delight, the yield of 8a could
rise to 97% and the reaction time could be dramatically reduced to
1 h and when NaOH was used as a base (entries 5, Table 3). It seems
that 3 equiv of NaOH were required to maintain the high yield
based on the results that 7a could not completely converted to the
desired product when 1 or 2 equiv of NaOH were employed (entries
6 and 7). The reactions also proceeded smoothly to afforded 8a in
20
a
Reactions were performed on a 0.5 mmol scale (102 mg) with inorganic bases
ꢀ
(3 equiv) and molecular sieves (4 A, ca. 200 wt %, 204 mg).
b
The reaction was performed with O2 (balloon) or open to air.
Isolated yields.
c

Y. Huang et al. / Tetrahedron 68 (2012) 3123e3128
Table 4 (continued)
3125
Table 3
The screening of reaction conditions of oxidation of imidazoline-5-carboxylamidea,b
Entry
Product
Conditionb Time (h) Yieldc (%)
A
B
2
2
91
96
7
Entry
Conditions
Temp (ꢀC)
Time (h)
Yieldc (%)
1
2
K2CO3 (3 equiv), O2
K2CO3 (3 equiv), O2
K2CO3 (3 equiv), O2
K2CO3 (3 equiv), O2
NaOH (3 equiv), O2
NaOH (2 equiv), O2
NaOH (1 equiv), O2
NaOH (3 equiv), O2
NaOH (3 equiv), O2
NaOH (3 equiv), O2
NaOH (3 equiv), air
80
100
120
120
120
120
120
100
80
36
36
36
36
1
24
24
1
23
27
40
35
97
80
62
93
95
97
95
A
B
1
1.5
94
94
8
3
4d
5
6
7
8
9
10
11
A
B
1
1
93
91
9
1
1
1
60
60
A
B
1
1
92
90
10
11
a
Reactions were performed on a 0.5 mmol scale (123 mg) with inorganic bases
(3 equiv).
b
c
The reaction was performed with O2 (balloon) or open to air.
Isolated yields.
A
B
1
1
94
94
d
ꢀ
Molecular sieves (4 A, ca. 200 wt %, 246 mg) was added.
excellent yields with either O2 or air in the presence of 3 equiv of
NaOH at lower temperatures (entries 8e11).
A
B
1
1
92
90
12
With the optimized conditions in hand, the oxidation of various
2-imidazoline-5-carboxamides to imidazole-5-carboxamides was
then examined as shown in Table 4. All substrates (7ael) bearing
electron-deficient or electron-rich aryl groups at 2-position could
be converted to the corresponding products (8ael) in nearly
quantitative yields under the optimized conditions (entries 1e12).
The reactions were quite efficient as all substrates could be fully
consumed in less than 2 h. The substituent on carboxamide group
did not much affect this conversion. Very gratifyingly, no obvious
difference was observed when air was used as an oxidant.
a
Reactions were performed in DMF on a 0.5 mmol scale with NaOH (3 equiv) at
60 ꢀC.
b
c
The reaction was performed with O2 (balloon) or open to air.
Isolated yields.
Finally, we set this protocol to the oxidation of 2-imidazole-5-
caboxylic derivatives in relatively large scale under the optimized
conditions. Indeed, treatment of 10 mmol of 5a under O2/K2CO3/
DMF condition at 100 ꢀC for 8 h smoothly provided the corre-
sponding product 6a in 91% isolated yield. Similarly, treatment of
10 mmol of 7a under O2/NaOH/DMF condition at 60 ꢀC for only 1.5 h
afforded 8a in almost quantitative isolated yield. These results
clearly indicate that our protocol is suitable for the synthesis of
imidazole-5-carboxylic derivatives in large scale (Scheme 2).
Table 4
Oxidation of 2-imidazoline-5-carboxylamides to imidazole-5-carboxylamides by
dioxygena,b
Entry
1
Product
Conditionb Time (h) Yieldc (%)
A
B
1
1
97
95
A
B
1
1
93
92
2
3
A
B
1
1
92
91
Scheme 2. The scalable oxidation of 2-imidazolines to 2-imidazoles by dioxygen.
A
B
2
2
93
93
4
5
6
3. Conclusions
A
B
1
1
95
92
We have first developed an efficient oxidation of 2-imidazoline-
5-carboxylic derivatives to imidazole-5-carboxylic derivatives by
dioxygen (1 atm) in very good to excellent yields. This process is
mild, environmental-benign and could provide a practical method
for the preparation of imidazole-containing molecules or natural
products. Moreover, our protocol could be applied to the synthesis
A
B
1
1
95
92

3126
Y. Huang et al. / Tetrahedron 68 (2012) 3123e3128
of imidazole-5-carboxylic derivatives in large scale, which must be
quite attractive to pharmaceutical industry. Further investigations
of this methodology for other heterocycles are now underway and
will be reported in due course.
134.1, 129.3, 129.1, 128.7, 127.7, 125.9, 51.5; HRMS (ESI) calcd for
[C11H9ClN2O2þH]þ 237.0425, found 237.0431.
4.2.5. Methyl 2-(4-bromophenyl)imidazole-5-carboxylate
(6e). White solid; mp 238e240 ꢀC; IR (KBr) 3469, 3167, 2954,
1717, 1598, 1479, 1336, 1196, 1115, 1067, 840, 804 cmꢁ1 1H NMR
;
4. Experimental
(300 MHz, CDCl3)
d
3.92 (s, 3H), 7.57 (d, J¼7.9 Hz, 2H), 7.81 (s, 1H),
7.82 (d, J¼7.9 Hz, 2H); 13C NMR (75 MHz, DMSO-d6)
d 163.2, 146.3,
4.1. General experimental
136.1, 132.3, 129.4, 127.8, 125.7, 122.7, 51.5; HRMS (ESI) calcd for
[C11H9BrN2O2þH]þ 280.9920, found 280.9924.
NMR spectra were recorded on a BRUKER-ACF-300 spectrome-
ter for 1H NMR at 300 MHz and for 13C NMR at 75 MHz. For 1H NMR,
4.2.6. Methyl 2-(4-trifluoromethylphenyl)imidazole-5-carboxylate
(6f). White solid; mp 230e232 ꢀC; IR (KBr) 3375, 3107, 2943,
tetramethylsilane (TMS) served as internal standard (
are reported as follows: chemical shift, integration, multiplicity
d
¼0) and data
1686, 1556, 1498, 1429, 1207, 1160, 1065, 849, 808 cmꢁ1 1H NMR
;
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
(300 MHz, DMSO-d6)
d
3.81 (s, 3H), 7.86 (d, J¼7.1 Hz, 2H), 8.07 (s,
br¼broad), and coupling constant in hertz. For 13C NMR, TMS (
¼0)
d
1H), 8.22 (d, J¼7.1 Hz, 2H), 13.45 (s, 1H); 13C NMR (75 MHz, DMSO-
or CDCl3
(
d
¼77.25) or DMSO-d6
(
d
¼39.51) was used as internal
d6) d 167.1, 163.2, 145.9, 133.9, 130.0, 129.5, 129.1, 128.8, 126.3, 125.6,
standard and spectra were obtained with complete proton decou-
pling. HRMS data were obtained on an Agilent 1100-LC-MSD-Trap/
SL spectrometer using ESI ionization. Mp data were measured with
a MEL-TEMP II micro melting point apparatus. IR spectra were
recorded on a BRUKER FT-IR TENSOR27 spectrometer (KBr).
122.8, 51.6; HRMS (ESI) calcd for [C12H10F3N2O2þH]þ 271.0689,
found 271.0696.
4.2.7. Methyl 2-(4-tolylphenyl)imidazole-5-carboxylate (6g). White
solid; mp 212e214 ꢀC; IR (KBr) 3232, 3025, 2946, 1721, 1693, 1499,
1345, 1278, 1164, 1012, 829 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 2.37
4.2. General procedure for the oxidation of 2-imidazoline-5-
carboxylates
(s, 3H), 3.90 (s, 3H), 7.21 (d, J¼8.1 Hz, 2H), 7.79 (s, 1H), 7.80 (d,
J¼8.1 Hz, 2H); 13C NMR (75 MHz, DMSO-d6)
d 163.5, 147.5, 138.9,
133.1, 129.8, 127.6, 125.8, 125.1, 51.4, 21.3; HRMS (ESI) calcd for
To a solution of 2-imidazoline-5-carboxylate (0.5 mmol,1 equiv)
in anhydrous DMF (5 mL) were added K2CO3 (207 mg, 1.5 mmol,
[C12H13N2O2þH]þ 217.0972, found 217.0972.
ꢀ
3 equiv) and molecular sieves (4 A, 200 wt %). The reaction mixture
4.2.8. Methyl 2-(4-methoxyphenyl)imidazole-5-carboxylate
was stirred with an O2 balloon or open to air at 100 ꢀC for 2.5e27 h.
The resulting solution was diluted with ethyl acetate and washed
with water and brine, dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel to afford imidazole-5-
carboxylate as a solid.
(6h). White solid; mp 213e215 ꢀC; IR (KBr) 3464, 3018, 2986,
1718, 1615, 1501, 1435, 1345, 1295, 1196, 843, 795 cmꢁ1 1H NMR
;
(300 MHz, CDCl3)
d
3.82 (s, 3H), 3.89 (s, 3H), 6.91 (d, J¼8.7 Hz, 2H),
7.83 (s, 1H), 7.85(d, J¼8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6)
d
160.4, 129.8, 127.5, 125.0, 123.0, 114.6, 114.0, 113.8, 55.7, 51.4;
HRMS (ESI) calcd for [C12H13N2O3þH]þ 233.0921, found 233.0925.
4.2.1. Methyl 2-phenylimidazole-5-carboxylate (6a). White solid;
mp 212e214 ꢀC; IR (KBr) 3442, 3079, 2944, 1728, 1655, 1561, 1457,
4.2.9. Methyl 2-(4-ethoxyphenyl)imiazole-5-carboxylate (6i). White
solid; mp 272e274 ꢀC; IR (KBr) 3449, 3086, 2927, 1722, 1616, 1501,
1481, 1385, 1282, 1198, 1042, 846 cmꢁ1; 1H NMR (300 MHz, CDCl3)
1435, 1384, 1284, 1127, 770, 695 cmꢁ1 1H NMR (300 MHz, CDCl3)
;
3.91 (s, 3H), 7.41e7.42 (m, 3H), 7.81 (s, 1H), 7.90e7.93 (m, 2H); 13C
d
1.43 (t, J¼7.0 Hz, 3H), 3.91 (s, 1H), 4.07 (q, J¼7.0 Hz, 2H), 6.94 (d,
NMR (75 MHz, DMSO-d6)
d
163.0, 147.8, 130.3, 129.4, 129.2, 126.0,
J¼8.6 Hz, 2H), 7.77(s, 1H), 7.86 (d, J¼8.6 Hz, 2H); 13C NMR (75 MHz,
125.3, 125.3, 51.5; HRMS (ESI) calcd for [C11H11N2O2þH]þ 203.0815,
DMSO-d6) d 159.6, 147.4, 136.5, 132.9, 127.3, 124.9, 122.8, 115.1, 63.6,
found 203.0821.
51.4, 15.0; HRMS (ESI) calcd for [C13H15N2O3þH]þ 247.1077, found
247.1085.
4.2.2. Methyl 2-(4-nitrophenyl)imidazole-5-carboxylate
(6b). Yellow solid; mp 286e288 ꢀC; IR (KBr) 3446, 3021, 2937,
4.2.10. n-Butyl 2-phenylimidazole-5-carboxylate (6j). White solid;
mp 123e124 ꢀC; IR (KBr) 3448, 3137, 2959, 1714, 1638, 1529, 1489,
1605, 1550, 1485, 1341, 1201, 1121, 1084, 855, 777 cmꢁ1 1H NMR
;
(300 MHz, DMSO-d6)
d
3.81 (s, 3H), 8.27e8.37 (m, 5H), 13.61 (s,1H);
1384, 1181, 716, 696 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 0.95 (t,
13C NMR (75 MHz, DMSO-d6)
d
162.6, 147.6, 145.8, 136.0, 129.4,
J¼7.0 Hz, 3H), 1.36e1.49 (m, 2H), 1.66e1.76 (m, 2H), 4.31 (q,
126.8, 124.6, 51.7; HRMS (ESI) calcd for [C11H10N3O4þH]þ 248.0666,
J¼6.5 Hz, 2H), 7.37e7.38 (m, 3H), 7.81 (s, 1H), 7.92e7.93 (m, 2H),
found 248.0673.
10.32 (br, 1H); 13C NMR (75 MHz, DMSO-d6)
d 162.5, 146.8, 133.0,
129.8, 128.8, 126.1, 125.3, 124.8, 63.1, 30.4, 18.7, 13.6; HRMS (ESI)
4.2.3. Methyl 2-(4-fluorophenyl)imidazole-5-carboxylate
(6c). White solid; mp 205e208 ꢀC; IR (KBr) 3446, 3168, 2937,
calcd for [C14H17N2O2þH]þ 245.1285, found 245.1296.
1697, 1516, 1436, 1341, 1201, 1121, 1084, 855, 777 cmꢁ1
;
1H NMR
4.2.11. n-Butyl 2-(4-trifluoromethylphenyl)imidazole-5-carboxylate
(6k). White solid; mp 216e218 ꢀC; IR (KBr) 3447, 3024, 2941,
(300 MHz, CDCl3)
d
3.92 (s, 3H), 7.14 (t, J¼7.7 Hz, 2H), 7.79 (s, 1H),
7.90 (t, J¼7.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6)
d
164.5, 163.3,
1722, 1622, 1501, 1438, 1283, 1169, 1095, 852, 836 cmꢁ1 1H NMR
;
161.3,146.5,136.4,133.2,128.9,128.1,128.0,126.9,125.5,116.4,116.1,
51.4; HRMS (ESI) calcd for [C11H10FN2O2þH]þ 221.0721, found
221.0727.
(300 MHz, DMSO-d6) d 0.89e0.97 (m, 3H), 1.37e1.48 (m, 2H),
1.65e1.73 (m, 2H), 4.23e4.24 (m, 2H), 7.85 (d, J¼8.0 Hz, 2H), 8.05 (s,
1H), 8.21 (d, J¼8.0 Hz, 2H), 13.42 (s, 1H); 13C NMR (75 MHz, DMSO-
d6) d 162.8, 145.9, 133.9, 130.0, 129.6, 129.1, 126.4, 126.2, 126.1, 122.8,
4.2.4. Methyl 2-(4-chlorophenyl)imidazole-5-carboxylate
63.8, 30.9, 19.1, 13.9; HRMS (ESI) calcd for [C15H16F3N2O2þH]þ
(6d). White solid; mp 210e212 ꢀC; IR (KBr) 3347, 3068, 2958,
313,1158, found 313.1175.
1710, 1483, 1367, 1266, 1157, 1091, 842, 804 cmꢁ1
;
1H NMR
(300 MHz, CDCl3)
d
3.92 (s, 3H), 7.42 (d, J¼8.5 Hz, 2H), 7.81 (s, 1H),
4.2.12. Ethyl 2-phenylimidazole-5-carboxylate (6l). White solid; mp
111e112 ꢀC; IR (KBr) 3463, 3144, 2995, 1715, 1638, 1571, 1488, 1369,
7.90 (d, J¼8.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6)
d 163.0, 146.5,

Y. Huang et al. / Tetrahedron 68 (2012) 3123e3128
3127
1285, 1185, 716, 697 cmꢁ1; 1H NMR (300 MHz, DMSO-d6)
d
1.49 (t,
4.3.6. N-n-Butyl-2-(4-methylphenyl)imidazole-5-carboxamide
(8f). White solid; mp 198e202 ꢀC; IR (KBr) 3342, 3139, 2953, 1630,
1557, 1462, 1383, 1296, 1148, 834 cmꢁ1; 1H NMR (300 MHz, CDCl3)
J¼6.7 Hz, 3H), 4.27 (q, J¼6.7 Hz, 2H), 7.40e7.51 (m, 3H), 7.97e7.98
(m, 2H), 8.12 (s, 1H), 13.13 (s, 1H); 13C NMR (75 MHz, DMSO-d6)
d
162.9, 147.3, 133.6, 130.3, 129.4, 129.2, 125.9, 125.3, 60.0, 14.8;
d
0.95 (t, J¼7.3 Hz, 3H),1.25e1.50 (m, 2H),1.58e1.69 (m, 2H), 2.39 (s,
HRMS (ESI) calcd for [C12H13N2O2þH]þ 217.0972, found 217.0982.
3H), 3.49 (q, J¼6.7 Hz, 2H), 7.25 (d, J¼8.2 Hz, 2H), 7.50 (s,1H), 7.62 (s,
1H), 7.92 (d, J¼8.2 Hz, 2H); 13C NMR (75 MHz, DMSO-d6)
d 162.0,
145.9, 138.1, 137.0, 129.2, 127.3, 125.2, 120.0, 37.9, 31.6, 20.8, 19.6,
13.6; HRMS (ESI) calcd for [C15H20N3OþH]þ 258.1601, found
258.1613.
4.3. Typical procedure for the oxidation of 2-imidazoline-5-
carboxamides
To
a
solution of 2-imidazoline-5-carboxamide (0.5 mmol,
4.3.7. N-n-Butyl-2-(4-methoxyphenyl)imidazole-5-carbox-amide
1 equiv) in anhydrous DMF (5 mL) was added NaOH (60 mg,
1.5 mmol, 3 equiv). The reaction mixture was stirred with an O2
balloon or open to air at 60 ꢀC for 1e2 h. The resulting solution was
diluted with dichloromethane, washed with water and brine, dried
over sodium sulfate, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel to afford imidazole-5- carboxamide as a solid.
(8g). White solid; mp 182e183 ꢀC; IR (KBr) 3475, 3118, 2965, 1632,
1570, 1552, 1473, 1299, 1207, 1182, 834, 795 cmꢁ1 1H NMR
;
(300 MHz, CDCl3)
d
0.94 (t, J¼7.3 Hz, 3H), 1.40e1.48 (m, 2H),
1.53e1.62 (m, 2H), 3.44 (q, J¼6.7 Hz, 2H), 3.87 (s, 3H), 6.97 (d,
J¼8.8 Hz, 2H), 7.15 (s, 1H), 7.52 (d, J¼8.8 Hz, 2H), 8.20 (s, 1H); 13C
NMR (75 MHz, DMSO-d6)
d 162.6, 160.1, 146.2, 137.4, 127.3, 123.3,
120.2, 114.6, 55.6, 38.4, 32.1, 20.1, 14.1; HRMS (ESI) calcd for
[C15H20N3O2þH]þ 274.1550, found 274.1564.
4.3.1. N-n-Butyl-2-phenylimidazole-5-carboxamide
solid; mp 220e222 ꢀC; IR (KBr) 3341, 3059, 2958, 1629, 1554, 1457,
1400, 1349, 1287, 1143, 779, 690 cmꢁ1 1H NMR (300 MHz, CDCl3)
0.95 (t, J¼7.3 Hz, 3H), 1.37e1.50 (m, 2H), 1.58e1.69 (m, 2H), 3.50
(8a). White
4.3.8. N-Cyclohexyl-2-(4-trifluoromethylphenyl)imidazole-5-
carboxamide (8h). White solid; mp 242e244 ꢀC; IR (KBr) 3399,
;
d
3162, 2961, 1647, 1581, 1516, 1441, 1330, 1284, 1162, 849, 795 cmꢁ1
;
(q, J¼6.8 Hz, 2H), 7.35e7.49 (m, 3H), 7.51 (s, 1H), 7.65 (s, 1H), 8.08 (d,
1H NMR (300 MHz, CDCl3)
d 1.26e1.40 (m, 5H), 1.67e1.81 (m, 3H),
J¼7.0 Hz, 2H), 12.67 (br, 1H); 13C NMR (75 MHz, DMSO-d6)
d
162.5,
2.04e2.05 (m, 2H), 4.01e4.10 (m, 1H), 7.43 (s, 1H), 7.67 (s, 1H), 7.70
146.0, 137.8, 130.5, 129.2, 129.1, 125.8, 120.6, 38.4, 32.1, 20.1, 14.2;
(d, J¼8.1 Hz, 2H), 8.26 (d, J¼8.1 Hz, 2H), 13.13 (s, 1H); 13C NMR
HRMS (ESI) calcd for [C14H18N3OþH]þ 244.1444, found 244.1458.
(75 MHz, DMSO-d6) d 160.9, 143.9, 137.7, 133.6, 129.1, 128.7, 128.3,
127.9, 126.1, 125.9, 125.7, 122.3, 121.2, 47.2, 32.5, 25.1, 24.8; HRMS
4.3.2. N-n-Butyl-2-(4-fluorophenyl)imidazole-5-carboxamide
(8b). White solid; mp 170e173 ꢀC; IR (KBr) 3412, 3181, 2961, 1639,
(ESI) calcd for [C17H19F3N3OþH]þ 338.1475, found 338.1490.
1579, 1494, 1373, 1226, 1162, 842, 814 cmꢁ1
;
1H NMR (300 MHz,
4.3.9. N-Cyclohexyl-2-(4-methylphenyl)imidazole-5-carboxamide
(8i). White solid; mp 246e248 ꢀC; IR (KBr) 3448, 3156, 2936, 1624,
1552, 1496, 1372, 1205, 1129, 830 cmꢁ1; 1H NMR (300 MHz, CDCl3)
CDCl3)
d
0.96 (t, J¼7.3 Hz, 3H), 1.38e1.51 (m, 2H), 1.59e1.70 (m, 2H),
3.50 (q, J¼6.8 Hz, 2H), 7.13 (t, J¼8.6 Hz, 2H), 7.46 (s, 1H), 7.63 (s, 1H),
8.08 (t, J¼8.6 Hz, 2H), 12.48 (br, 1H); 13C NMR (75 MHz, DMSO-d6)
d
1.20e1.47 (m, 5H), 1.64e1.77 (m, 3H), 2.01e2.05 (m, 2H), 2.39 (s,
d
164.4, 162.4, 161.1, 145.2, 137.7, 128.0, 127.9, 127.2, 120.7, 116.3,
1H), 3.97e3.98 (m, 1H), 7.43 (s, 1H), 7.67 (s, 1H), 7.24 (d, J¼8.2 Hz,
116.0, 38.3, 32.1, 20.1, 14.1; HRMS (ESI) calcd for [C14H17FN3OþH]þ
2H), 7.37 (s,1H), 7.61 (s,1H), 7.92 (d, J¼8.2 Hz, 2H),11.84 (br,1H); 13C
262.1350, found 262.1362.
NMR (75 MHz, DMSO-d6) d 161.2, 145.6, 138.1, 137.0, 129.2, 127.3,
125.2, 120.0, 47.1, 32.5, 25.2, 24.9, 20.8; HRMS (ESI) calcd for
4.3.3. N-n-Butyl-2-(4-chlorophenyl)imidazole-5-carboxamide
(8c). White solid; mp 174e175 ꢀC; IR (KBr): 3396, 3137, 2959, 1642,
1582, 1484, 1383, 1286, 1131, 835 cmꢁ1; 1H NMR (300 MHz, CDCl3)
[C17H22N3OþH]þ 284.1757, found 284.1759.
4.3.10. N-n-Propyl-2-phenylimidazole-5-carboxamide (8j). White
solid; mp 230e234 ꢀC; IR (KBr) 3464, 3142, 2964, 1629, 1561, 1457,
d
0.97 (t, J¼7.3 Hz, 3H),1.38e1.51 (m, 2H),1.60e1.70 (m, 2H), 3.50 (q,
J¼6.7 Hz, 2H), 7.42 (d, J¼8.5 Hz, 2H), 7.48 (s,1H), 7.62 (s,1H), 8.04 (d,
1347, 1295, 1147, 781, 693 cmꢁ1 1H NMR (300 MHz, DMSO-d6)
;
J¼8.5 Hz, 2H), 12.67 (br, 1H); 13C NMR (75 MHz, DMSO-d6)
d
162.4,
d
0.88 (t, J¼7.3 Hz, 3H), 1.46e1.59 (m, 2H), 3.21 (q, J¼6.7 Hz, 2H),
7.35e7.50 (m, 3H), 7.71 (s, 1H), 7.87 (s, 1H), 8.04 (d, 2H), 12.91 (br,
1H); 13C NMR (75 MHz, DMSO-d6)
162.0, 145.7, 137.1, 130.0, 128.7,
144.9, 137.9, 133.7, 129.4, 129.3, 127.4, 121.0, 38.3, 32.1, 20.1, 14.2;
HRMS (ESI) calcd for [C14H17ClN3OþH]þ 278.1055, found 278.1067.
d
128.6, 125.3, 120.2, 40.0, 22.7, 11.3; HRMS (ESI) calcd for
4.3.4. N-n-Butyl-2-(4-bromophenyl)imidazole-5-carboxamide
[C13H16N3OþH]þ 230.1288, found 230.1289.
(8d). White solid; mp 173e174 ꢀC; IR (KBr) 3375, 3132, 2957, 1646,
1579, 1509, 1480, 1384, 1287, 1200, 1131, 835 cmꢁ1
;
1H NMR
4.3.11. N-n-Propyl-2-(4-trifluoromethylphenyl)imidazole-5-
carboxamide (8k). White solid; mp 230e232 ꢀC; IR (KBr) 3449,
3204, 2973, 2891, 1638, 1560, 1550, 1431, 1384, 1328, 1160, 1126,
(300 MHz, CDCl3)
d
0.95 (t, J¼7.3 Hz, 3H), 1.36e1.44 (m, 2H),
1.54e1.62 (m, 2H), 3.44 (q, J¼6.7 Hz, 2H), 7.10 (s, 1H), 7.44 (d,
J¼8.4 Hz, 2H), 7.61 (d, J¼8.4 Hz, 2H), 8.23 (s, 1H); 13C NMR (75 MHz,
842, 706 cmꢁ1
; d 0.88 (t,
1H NMR (300 MHz, DMSO-d6)
DMSO-d6)
d
162.4, 145.0, 137.9, 132.2, 129.7, 127.7, 122.3, 121.0, 38.3,
J¼7.3 Hz, 3H), 1.47e1.58 (m, 2H), 3.22 (q, J¼6.6 Hz, 2H), 7.81 (s,
32.1, 20.1, 14.2; HRMS (ESI) calcd for [C14H17BrN3OþH]þ 322.0550,
1H), 7.86 (d, J¼8.1 Hz, 2H), 7.95 (s, 1H), 8.21 (d, J¼8.1 Hz, 2H),
found 322.0561.
13.21 (s, 1H); 13C NMR (75 MHz, DMSO-d6)
d 162.4, 144.5, 138.3,
134.2, 130.0, 129.3, 129.2, 128.8, 128.4, 126.4, 126.2, 122.8, 119.2,
121.5, 40.5, 23.2, 11.8; HRMS (ESI) calcd for [C14H15F3N3OþH]þ
298.1162, found 298.1164.
4.3.5. N-n-Butyl-2-(4-trifluoromethylphenyl)imidazole-5-carbo-xa-
mide (8e). White solid; mp 193e194 ꢀC; IR (KBr) 3404, 3137, 2962,
1632, 1581, 1522, 1438, 1325, 1219, 1140, 849 cmꢁ1 1H NMR
;
(300 MHz, CDCl3)
d
0.96 (t, J¼7.3 Hz, 3H), 1.38e1.52 (m, 2H),
4.3.12. N-n-Propyl-2-(4-methoxyphenyl)imidazole-5-carboxamide
1.61e1.72 (m, 2H), 3.53 (q, J¼6.7 Hz, 2H), 7.54 (s, 1H), 7.67 (s, 1H),
(8l). White solid; mp 198e200 ꢀC; IR (KBr) 3205, 3058, 2959, 1632,
7.70 (d, J¼8.3 Hz, 2H), 8.26 (d, J¼8.3 Hz, 2H), 13.15 (br, 1H); 13C NMR
1571, 1524, 1437, 1385, 1311, 1208, 834, 796 cmꢁ1
;
1H NMR
(75 MHz, DMSO-d6)
d
162.3, 144.4, 138.3, 134.2, 129.6, 129.2, 128.8,
(300 MHz, DMSO-d6)
d
0.92 (t, J¼7.3 Hz, 3H),1.53e1.61 (m, 2H), 3.25
126.2, 122.8, 121.5, 38.4, 32.0, 20.1, 14.1; HRMS (ESI) calcd for
(q, J¼6.2 Hz, 2H), 3.85 (s, 3H), 7.07 (d, J¼8.5 Hz, 2H), 7.69 (s,1H), 7.97
[C15H17FN3OþH]þ 312.1318, found 312.1331.
(s, 1H), 7.98 (d, J¼8.5 Hz, 2H), 12.79 (s, 1H); 13C NMR (75 MHz,

3128
Y. Huang et al. / Tetrahedron 68 (2012) 3123e3128
4. For imidazoles: (a) Grimmett, M. R. In Comprehensive Heterocyclic Chemistry;
DMSO-d6) d 162.3, 160.1, 146.4, 137.4, 127.3, 123.3, 120.2, 114.6, 55.6,
Potts, K. T., Ed.; Pergamon: Oxford, 1984; Vol. 4, p 345; (b) Chen, X. Z.; Xu, P.;
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Bioorg. Med. Chem. Lett. 2011, 21, 182.
40.5, 23.2, 11.8; HRMS (ESI) calcd for [C14H18N3O2þH]þ 260.1394,
found 260.1409.
5. Lauwagie, S.; Millet, R.; Pommery, J.; Depreux, P.; Henichart, J. P. Heterocycles
2006, 68, 1149.
6. Dockner, T.; Frank, A. Ger. Offen. 2,729,017, 1979; Chem. Abstr. 1979, 204100.
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11. Hughey, J. L.; Knapp, S.; Schudar, H. Synthesis 1980, 489.
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Acknowledgements
Financial supports from State key Laboratory of Natural Medi-
cines (JKGZ201110), the National Natural Science Foundation (No.
20902111), NCET 2008 and Fok Ying Tong Education Foundation
(121040) by the Ministry of Education of China, and Fundamental
Research Funds for the Central Universities (JKZ2009002 and
JKY2009013) are highly appreciated.
14. Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew. Chem., Int. Ed. 2003, 42,
4077.
15. Ishihara, M.; Togo, H. Synlett 2006, 277.
Supplementary data
16. (a) Kargar, H.; Moghadam, M.; Mirkhani, V.; Tangestaninejad, S.; Mo-
hammadpoor-Baltork, I.; Naghipour, M. Polyhedron 2011, 30, 1463; (b) Kargar, H.
Inorg. Chem. Commun. 2011, 14, 863.
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Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.01.025.
18. Su, F.; Mathew, S. C.; Mohlmann, L.; Antonietti, M.; Wang, X.; Blechert, S. Angew.
Chem., Int. Ed. 2011, 50, 657.
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D. C., Ed.; John Wiley: Hoboken, NJ, 2003; (b) Oxazoles: Synthesis, Reactions and
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20. For the synthesis of 2-imidazoline-5-carboxylates: Jones, R. C. F.; Ward, G. J.
Tetrahedron Lett. 1988, 29, 3853.